title: Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics.
abstract: In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available.
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Shigeo
authors.initials: S
authors.lastname: Matsuda
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.forename: Scott
authors.initials: S
authors.lastname: Barros
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Ying K
authors.initials: YK
authors.lastname: Tam
authors.forename: Steven M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Varun
authors.initials: V
authors.lastname: Kumar
authors.forename: June
authors.initials: J
authors.lastname: Qin
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Qianfan
authors.initials: Q
authors.lastname: Wang
authors.forename: Sue
authors.initials: S
authors.lastname: Panesar
authors.forename: Renta
authors.initials: R
authors.lastname: Hutabarat
authors.forename: Mary
authors.initials: M
authors.lastname: Carioto
authors.forename: Julia
authors.initials: J
authors.lastname: Hettinger
authors.forename: Pachamuthu
authors.initials: P
authors.lastname: Kandasamy
authors.forename: David
authors.initials: D
authors.lastname: Butler
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.forename: Bo
authors.initials: B
authors.lastname: Pang
authors.forename: Klaus
authors.initials: K
authors.lastname: Charisse
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Mui
authors.forename: Xinyao
authors.initials: X
authors.lastname: Du
authors.forename: Pieter
authors.initials: P
authors.lastname: Cullis
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Madden
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hope
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
mesh_terms: D000818:Animals; D002460:Cell Line; D016503:Drug Delivery Systems; D005167:Factor VII / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008055:Lipids / Q000737:chemistry* / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics*; D051381:Rats
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D005167:Factor VII